CN103601670B - The similar thing of piperlongumine and its preparation method and application - Google Patents

The similar thing of piperlongumine and its preparation method and application Download PDF

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CN103601670B
CN103601670B CN201310566990.0A CN201310566990A CN103601670B CN 103601670 B CN103601670 B CN 103601670B CN 201310566990 A CN201310566990 A CN 201310566990A CN 103601670 B CN103601670 B CN 103601670B
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hydrogen
trimethoxy
pyridone
indole
carbonyl
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CN103601670A (en
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缪震元
张万年
吴岳林
盛春泉
姚建忠
庄春林
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to medical art, piperlongumine (Piplartine) is a kind of alkaloid pulling out middle extraction from piperaceae Piper herbaceous perennial vine plant Bi. The present invention provides a similar thing of class piperlongumine, comprises any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, and structure is as shown in general formula (I):

Description

The similar thing of piperlongumine and its preparation method and application
Technical field
The present invention relates to medical art, it is specifically related to a class and replaces Piperlongumine compounds and its preparation method, and in the application prepared in antitumor drug.
Background technology
Piperlongumine (Piplartine) is a kind of alkaloid pulling out middle extraction from piperaceae Piper herbaceous perennial vine plant Bi, and its chemical structure is as follows:
Pharmacological testing shows that piperlongumine has multiple biological activity, as the treatment of neural system aspect disease, the treatment of cardiovascular and cerebrovascular diseases and antimycotic, antidepressant and antitumor action. WO2008147483 and WO2009038684 respectively describes piperlongumine and analogue is treating the multiple demyelinating disease of Progressive symmetric erythrokeratodermia central nervous system such as the effect of Progressive symmetric erythrokeratodermia many stoves leukoencephalopathy and the nervous tissue relative disease of hippocampus damage initiation. Piperlongumine has the effect falling blood pressure, and is highly resistant to the gathering of thrombocyte, can be used for the treatment (Phytomedicine2007,14:853 of cardiovascular and cerebrovascular diseases; JournalofPharmacology2007,57:380), CN200910243046 and CN201010033836 respectively describe the similar thing of piperlongumine synthetic method and in the application of thrombus prevention and cure medicine. In addition, piperlongumine also has good fungi restraining effect (Phytochemistry, 2000,55:621; Crop.Prto, 2001,20:523), there is certain antidepressant effect (Phytomedicine, 2007,14:605).
WO2009114126 describes piperlongumine and analogue plays the effect treating tumour by affecting reactive oxygen species in tumour cell, and CN102125552 reports the antitumor action to the piperlongumine alkoxyl group substitutive derivative after piperlongumine structural modification subsequently. The similar thing of piperlongumine of these reports is active relatively not high, it is therefore desirable to carry out further structural modification, strengthens anti-tumor activity and selectivity, the reduction toxicity of compound, therefrom researches and develops the antitumor drug of novel mechanism.
Summary of the invention
It is an object of the invention to provide a class and replace Piperlongumine compounds, it is a further object of the present invention to provide the preparation method of described replacement Piperlongumine compounds, and in the application prepared in antitumor drug.
Existing piperlongumine structural modification mainly concentrates on phenyl ring alkoxyl group and replaces part and lactam nucleus, and there is no correlative study for piperlongumine lactan and double bond replace, the technical scheme of the present invention mainly replaces part and lactam ring structure at reservation piperlongumine phenyl ring alkoxyl group, by introducing substituted radical at lactan and double bond, obtain a class similar thing of novel piperlongumine.
A first aspect of the present invention, it provides a similar thing of class piperlongumine, comprises any mixture or its pharmaceutical salts of its cis-trans-isomer and its these forms, and structure is as shown in general formula (I):
In formula (I):
R1Represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, hydrazine base, azido-, low alkyl group, low-grade halogenated alkyl, lower alkoxy or R1And R2Forming the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH2, O, S or NR5;
Preferred R1Represent following groups: hydrogen, hydroxyl, amino, halogen or R1And R2Forming the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH2, O, S or NR5;
R2Represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, hydrazine base, azido-, low-grade alkyl amino, low alkyl group, low-grade halogenated alkyl, lower alkoxy, low-grade alkenyl, rudimentary cyanoalkyl, rudimentary 4-nitro alkyl, amide group, rudimentary amido alkyl, rudimentary hydrazine base alkyl, rudimentary azido-alkyl, (CH2)mNR5R6、(CH2)mOR7、(CH2)mSR8、(CH2)mNR5C(O)R7、(CH2)mC(O)R7、(CH2)mOC(O)R7、O(CH2)mNR5R6、OC(O)NR5、OC(O)(CH2)mOC(O)R7, or R1And R2Forming the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH2, O, S or NR5;
Preferred R2Represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy or R1And R2Forming the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH2, O, S or NR5;
R3Represent following groups: hydrogen, hydroxyl, amino, halogen, cyano group, hydrazine base, azido-, low-grade alkyl amino, low alkyl group, low-grade halogenated alkyl, lower alkoxy, low-grade alkenyl, rudimentary cyanoalkyl, rudimentary 4-nitro alkyl, amide group, rudimentary amido alkyl, rudimentary hydrazine base alkyl, rudimentary azido-alkyl, (CH2)mNR5R6、(CH2)mOR7、(CH2)mSR8、(CH2)mNR5C(O)R7、(CH2)mC(O)R7、(CH2)mOC(O)R7、O(CH2)mNR5R6、OC(O)NR5、OC(O)(CH2)mOC(O)R7;
Preferred R3Represent following groups: hydrogen, halogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy;
R4Represent following groups: hydrogen, amino, halogen, cyano group, amide group, azido-, hydrazine base, low alkyl group, low-grade halogenated alkyl, lower alkoxy, low-grade alkenyl, (CH2) n [N=X], OC (O) [N=X], (CH2) mOC (O) [N=X] (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom N, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH2、CH、NR5), substituted or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy;
Preferred R4Represent following groups: hydrogen, amino, halogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy, (CH2) (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom N to n [N=X], and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH2、CH、NR5);
R5、R6、R7、R8Independently representing hydrogen, hydroxyl, amino, halogen, low alkyl group, rudimentary hydroxyalkyl, rudimentary amido alkyl, low-grade alkenyl, lower alkoxy, low-grade halogenated alkyl or substituted or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, halogen, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
Preferred R5、R6、R7、R8Independently represent hydrogen, low alkyl group;
M is the integer between 0 to 3;
N is 1 or 2;
Herein, the term " rudimentary " relevant with alkyl, alkylthio and alkoxyl group refers to the straight or branched saturated fatty hydrocarbyl group containing 1 to 6 carbon atom, such as, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methylthio group, ethylmercapto group, methoxyl group and oxyethyl group, the term " rudimentary " relevant with term alkenyl or alkynyl group refers to the group containing 2 to 6 carbon atoms and one or more double bond or triple bond, such as: vinyl, allyl group, different allyl group, pentenyl, hexenyl, propenyl, ethynyl, proyl and butynyl. Term cycloalkyl refers to the ring containing 3 to 7 carbon, such as, and cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Term aryl refers to list, two or tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, each ring containing maximum 7 carbon atoms, such as, phenyl, naphthyl, anthryl, xenyl or indenyl. term halogen refers to chlorine, bromine, iodine or fluorine. corresponding to term low-grade halogenated alkyl, rudimentary cyanoalkyl, rudimentary 4-nitro alkyl, rudimentary amido alkyl, rudimentary hydrazine base alkyl, lower alkoxy low alkyl group, rudimentary azido-alkyl, rudimentary aralkyl, rudimentary hydroxyalkyl, the group of lower alkylthio low alkyl group and the rudimentary alkylsulfonyl alkyl of low alkyl group is respectively by one to three halogen, cyano group, nitro, amide group, hydrazine base, alkoxyl group, azido-, aryl, hydroxyl, low-grade alkyl sulphur base low alkyl group or rudimentary alkylsulfonyl alkyl replace. low-grade alkyl amino can contain one or two low alkyl group, such as, represent NHCH3、NHCH2CH3、N(CH3)2Or CH3NCH2CH3。
Preferably, in formula (I):
R1Represent following groups: hydrogen, hydroxyl, amino, halogen or R1And R2Forming the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH2, O, S or NR5;
R2Represent following groups: hydrogen, hydroxyl, amino, halogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy or R1And R2Forming the chain of 5 or 6 yuan together, wherein the unit of this chain is selected from CH, CH2, O, S or NR5;
R3Represent following groups: hydrogen, halogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy;
R4Represent following groups: hydrogen, amino, halogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy, (CH2) (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom N to n [N=X], and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH2、CH、NR5);
R5、R6、R7、R8Independently represent hydrogen, low alkyl group, cycloalkyl;
M is the integer between 0 to 3;
N is 1 or 2;
The term " rudimentary " relevant to alkyl and alkoxyl group refers to the straight or branched saturated fatty hydrocarbyl group containing 1 to 6 carbon atom, and term " halogen " refers to chlorine, bromine, iodine or fluorine, corresponding to term low-grade halogenated alkyl by one to three halogen substiuted.
More excellent, formula I is selected from:
(E) the chloro-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E)-3-morpholine-1-(3-(3,4,5-p-methoxy-phenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E)-1-(2-methyl-3-(3,4,5-p-methoxy-phenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E)-1-(2-(3,4,5-anisole methylene radical) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one,
(E) the chloro-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the chloro-1-of-3-(2-(3,4,5-anisole methylene radical) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one,
(E) the chloro-1-of-3-(2-(3,4,5-anisole methylene radical) pentanoyl)-5,6-dihydropyridine-2 (1H)-one,
(E)-1-(2-methyl-3-(3,4,5-p-methoxy-phenyl) acryl)-3-morpholinyl-5,6-dihydropyridine-2 (1H)-one,
(E)-3-morpholinyl-1-(2-(3,4,5-anisole methylene radical) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one,
(E)-3-morpholinyl-1-(2-(3,4,5-anisole methylene radical) pentanoyl)-5,6-dihydropyridine-2 (1H)-one,
1-(5,6,7-trimethoxy-1-methyl isophthalic acid H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-bromotrifluoromethane-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-benzyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-methyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone,
(E) the chloro-1-of-3-(2-butyl-(3; 4; 5-trimethoxyphenyl) acryl)-5; 6-dihydropyridine-2 (1H)-one, 1-(5; 6; 7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
(E) the bromo-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
1-(5,6,7-trimethoxy-1-methyl isophthalic acid H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
The chloro-1-of 3-(5,7-dimethoxy-1-methyl-6-(the third-2-alkynyloxy group)-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, or
1-(5,7-dimethoxy-1-methyl-6-(the third-2-alkynyloxy group)-1H-indole-2-carbonyl)-3-morpholine-5,6-two hydrogen-2 (1H)-pyridone.
Research shows, the methyl in piperlongumine alkoxy grp can be replaced by groups such as hydrogen, ethyl, propyl group, benzyl, halogen, amino, polyethylene group, alkyl substituted amidos, still can keep original activity. Therefore above-mentioned structural modification is suitable for the present invention too, also can obtain the similar thing of the piperlongumine with anti-tumor activity by similar modification.
Described pharmaceutical salts, refers to the salt of pharmaceutically acceptable various form, it is possible to the salt that the organic acid such as mineral acid or toxilic acid, oxysuccinic acid, citric acid such as hydrochloric acid, nitric acid, Hydrogen bromide is formed.
A second aspect of the present invention, is to provide the preparation method of a described similar thing of class piperlongumine. Taking 2-piperidone as raw material, first synthesize unsaturated six membered lactams rings, then prepare the various acyl chlorides that trimethoxyphenyl replaces, both are reacted and prepares the similar thing of piperlongumine.
A third aspect of the present invention, is to provide a described similar thing of class piperlongumine, comprises any mixture of its cis-trans-isomer and its these forms or its pharmaceutical salts in the application preparing in antitumor drug.
The compound of the present invention has anti-tumor activity, they can be used for treatment tumour, comprise the cancer that the positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system occur, and thyroid carcinoma, leukemia, suddenly Jin Shi disease, lymphoma and myelomatosis etc.
The pharmacologically active of the compounds of this invention makes it may be used for antitumor, antimycotic, the platelet aggregation-against of preparation and anti-neural system medicine, and therefore the present invention also comprises using these compounds and pharmaceutical salts thereof as the pharmaceutical composition of activeconstituents. This pharmaceutical composition can be solid form or liquid form.
The compound of the present invention, comprise any mixture of its cis-trans-isomer and its these forms or its pharmaceutical salts except in the application preparing in antitumor drug, also can be used for preparing agents: antifungal drug, medicament for resisting platelet aggregation, antidepressant drug, anxiolytic medicament, analgesic, and the medicine etc. of other cardiovascular and cerebrovascular diseases and nervous system disorders.
Embodiment
Now in conjunction with the embodiments, the invention will be further described, but the enforcement of the present invention is not limited in this.
The synthesis of embodiment 1:3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone
25.0 grams of 2-piperidone are dissolved in 250 milliliters of chloroforms, are cooled to 0 degree, add 158.0 grams of phosphorus pentachlorides, stir 15 minutes, then heating reflux reaction 3 hours. Slowly being poured into by reaction solution after cooling in 500 milliliters of frozen water, water layer methylene dichloride 50 milliliters extracts 3 times, merges organic phase, saturated brine It, dry, boils off solvent and obtains yellow oily liquid.
4.0 grams of upper step products are dissolved in 12 milliliters of DMF, add 3.6 grams of anhydrous Quilonum Retards, react 7 hours under 120 degree. Pouring into after cooling in frozen water, extract 3 times with methylene dichloride 50 milliliters, saturated common salt water washing, dry, concentrated, raffinate purification by column chromatography obtains product 1.1 grams, receipts rate 35.1%.
1H-NMR(CDCl3):7.11-7.27(m,1H),6.78(t,1H),3.45-3.50(m,2H),2.44-2.50(m,2H)。
The preparation of embodiment 2:3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone
1.3 grams of 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridones and 0.9 gram of morpholine are dissolved in 5 milliliters of DMF, add 1.5 grams of anhydrous Quilonum Retards, be warming up to 130 degree, react 3 hours.Filtering, pressure reducing and steaming solvent, raffinate purification by column chromatography obtains 0.6 gram of white solid, receipts rate 30.2%.
1H-NMR(CDCl3):6.15(s,1H),5.56(t,1H),3.82-3.85(m,4H),3.30-3.36(m,2H), 2.87-2.90(m,4H),2.33-2.40(m,2H)。
Embodiment 3:(E)-2-methyl-3-(3,4,5-trimethoxyphenyl) acrylic acid preparation
2.0 grams of TMBs, 5.9 grams of 2-Methylpropanedioic acids, 0.2 gram of piperidines and 20 milliliters of anhydrous pyridines are joined in flask, back flow reaction 24 hours. Pressure reducing and steaming solvent, raffinate adds 50 ml waters and dissolves, and extracts 3 times by ethyl acetate 20 milliliters, washing, and dry, raffinate purification by column chromatography obtains white solid 1.7 grams, receipts rate 66.1%.
1H-NMR(CDCl3):7.77(s,1H),6.69(s,2H),3.10(s,9H),2.19(s,3H).
Embodiment 4:(E)-2-ethyl-3-(3,4,5-trimethoxyphenyl) acrylic acid preparation
According to the method for embodiment 3, replace 2-Methylpropanedioic acid with 2-ethyl malonic acid, obtain 1.4g pale solid, receipts rate 53.0%.
1H-NMR(CDCl3):7.74(s,1H),6.69(s,2H),3.91(s,3H),3.90(s,6H),2.63(q,2H),1.27(t,3H,).
Embodiment 5:(E)-2-propyl group-3-(3,4,5-trimethoxyphenyl) acrylic acid preparation
According to the method for embodiment 3, replace 2-Methylpropanedioic acid with 2-propylmalonic acid, obtain 1.0g pale solid, receipts rate 36.0%.
1H-NMR(CDCl3):7.73(s,1H),6.67(s,2H),3.90(s,3H),3.88(s,6H),2.55-2.58(m,2H),1.64-1.69(m,2H),1.03(t,3H).
Embodiment 6:(E) preparation of-3-(3,4,5-trimethoxyphenyl)-2-butylene acid
0.66 gram of phosphine acyl acetic acid three ethyl is dissolved in 10 milliliters of anhydrous tetrahydro furans, after being cooled to 0 degree, adds 0.08 gram of sodium hydride, stirring at room temperature 15 minutes; drip and add 0.42 gram 3 that is dissolved in 10 milliliters of tetrahydrofuran (THF)s; 4,5-trimethoxy methyl phenyl ketone solution, back flow reaction 10 hours. Cool to room temperature, the cancellation that adds water is reacted, ethyl acetate 20 milliliters extraction 3 times, and washing is dry, boils off solvent, adds 0.05 gram of lithium hydroxide and 20 milliliters of THF/H2O (3:1) mixed solvent room temperature reaction spends the night, and boils off solvent, and adjust ph is 2, ethyl acetate 20 milliliters extraction 3 times, washes with water and saturated nacl aqueous solution washing respectively, dry, drying, raffinate purification by column chromatography obtains white solid 0.38 gram, receipts rate 76.3%.
1H-NMR(CDCl3):6.71(s,2H),6.15(d,1H),3.91(s,6H),3.89(s,3H),2.59(d,3H).
The preparation of embodiment 7:5,6,7-trimethoxy-1-methyl isophthalic acid H-Indoline-2-carboxylic acid
2.5 grams of 5,6,7-trimethoxy-1H-indole-2-carboxylic methyl esters are dissolved in 60 milliliters of DMSO, add 1.0 grams of KOH, reaction 1.5 hours under 25 degree, then add 0.6 milliliter of methyl iodide and continue reaction 1.5 hours. Pouring in frozen water, precipitate out solid, filter, washing, adds 0.05 gram of lithium hydroxide and 20 milliliters of THF/H2O (3:1) mixed solvent room temperature reaction spends the night, and boils off solvent, and adjust ph is 2, ethyl acetate 20 milliliters extraction 3 times, washes with water and saturated nacl aqueous solution washing respectively, dry, drying, raffinate purification by column chromatography obtains white solid 2.1 grams, receipts rate 84.0%.
1H-NMR(CDCl3):12.72(s,1H),7.09(s,1H),6.94(s,1H),3.90(s,3H),3.78-3.79(m,6H).
Embodiment 8:(E) preparation of the chloro-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
119.0mg3,4,5-trimethoxy cinnamic acid, 254.0mg oxalyl chloride and 5 milliliters of anhydrous tetrahydro furans are joined in flask, reacts 4 hours under nitrogen protection, be cooled to 0 degree, drip and add 101.0mg triethylamine, after having dripped, continue reaction 15 minutes at 0 degree. Then drip to add and it is dissolved in 5 milliliters of anhydrous tetrahydro furans 66.0mg3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, stirring at room temperature adds 30 milliliters of methylene dichloride after 12 hours, saturated ammonium chloride, saturated nacl aqueous solution wash respectively, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, raffinate purification by column chromatography obtains white solid 98.5mg, receipts rate 56.0%.
1H-NMR(CDCl3):7.73(d,1H),7.45(d,1H),7.11(t,1H),6.83(s,2H),4.12(t,2H),3.90-3.92(m,9H),2.57-2.60(m,2H).EI-MS:m/z:352.2[M+H]+.
Embodiment 9:(E) preparation of-3-morpholine-1-(3-(3,4,5-p-methoxy-phenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, replace 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone with 3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone, obtain 90.5mg off-white color solid, receipts rate 45.0%.
1H-NMR(CDCl3):7.67(d,1H),7.45(d,1H),6.80(s,2H),6.18-6.20(m,1H,),3.94(t,2H),3.87-3.89(m,13H),2.61-2.68(m,4H),2.94-2.97(m,4H),2.45-2.48(m,2H).EI-MS:m/z:403.2[M+H]+.
Embodiment 10:(E) preparation of-1-(2-methyl-3-(3,4,5-p-methoxy-phenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, with (E)-2-methyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 124.7mg off-white color solid, receipts rate 75.3%.
1H-NMR(CDCl3):8.07-8.11(m,1H),7.55-7.74(m,1H),7.45-7.50(m,1H),6.77(s,1H),6.67(s,1H),3.87-3.93(m,9H),2.38-2.39(m,2H),2.17(s,3H).EI-MS:m/z:332.0[M+H]+.
Embodiment 11:(E)-1-(2-(3,4,5-anisole methylene radical) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, with (E)-2-ethyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 123.6mg off-white color solid, receipts rate 71.6%.
1H-NMR(CDCl3):6.91-6.94(m,1H),6.70(s,1H),6.56(s,2H),5.99(d,1H),3.93(t,2H),3.85(s,9H),2.63(q,2H),2.51-2.54(m,2H),1.13(t,3H).EI-MS:m/z:346.1[M+H]+.
Embodiment 12:(E) preparation of the chloro-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, replace 3,4,5-trimethoxy cinnamic acid with (E)-2-methyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 97.5mg off-white color solid, receipts rate 53.3%.
1H-NMR(CDCl3):7.10(t,1H),6.90(s,1H),6.63(s,2H),3.96(t,2H),3.87(s,9H),2.64(q,2H),2.15(s,3H).EI-MS:m/z:366.3[M+H]+.
Embodiment 13:(E) preparation of the chloro-1-of-3-(2-(3,4,5-anisole methylene radical) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, replace 3,4,5-trimethoxy cinnamic acid with (E)-2-ethyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 94.4mg off-white color solid, receipts rate 49.7%.
1H-NMR(CDCl3):7.07(t,1H),6.74(s,1H),6.56(s,2H),3.96(t,2H),3.86(s,3H),3.85(s,6H),2.61-2.68(m,4H),1.14(t,3H).EI-MS:m/z:418.3[M+K]+.
Embodiment 14:(E) preparation of the chloro-1-of-3-(2-(3,4,5-anisole methylene radical) pentanoyl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, replace 3,4,5-trimethoxy cinnamic acid with (E)-2-propyl group-3-(3,4,5-trimethoxyphenyl) vinylformic acid, obtain 81.9mg off-white color solid, receipts rate 41.6%.
1H-NMR(CDCl3):7.05(t,1H),6.69(s,1H),6.48(s,2H),3.96(t,2H),3.86(s,3H),3.85(s,6H),2.59-2.65(m,4H),δ1.64-1.69(m,2H),δ1.03(t,3H).EI-MS:m/z:394.2[M+H]+.
Embodiment 15:(E) preparation of-1-(2-methyl-3-(3,4,5-p-methoxy-phenyl) acryl)-3-morpholinyl-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, with (E)-2-methyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid and 3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 141.0mg off-white color solid, receipts rate 67.8%.
1H-NMR(CDCl3):6.86(s,1H),6.63(s,2H),5.99-5.60(m,1H),3.80-3.90(m,15H),2.88-2.89(m,4H),2.50-2.53(m,2H),2.16(s,3H).EI-MS:m/z:417.4[M+H]+.
Embodiment 16:(E) preparation of-3-morpholinyl-1-(2-(3,4,5-anisole methylene radical) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, with (E)-2-ethyl-3-(3,4,5-trimethoxyphenyl) vinylformic acid and 3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 135.9mg off-white color solid, receipts rate 63.2%.
1H-NMR(CDCl3):6.70(s,1H),6.58(s,2H),5.92(t,1H),3.84-3.88(m,11H),3.81(t,4H),2.86(t,4H),2.65(q,2H),2.50(q,2H),1.12(t,3H).EI-MS:m/z:431.2[M+H]+.
Embodiment 17:(E) preparation of-3-morpholinyl-1-(2-(3,4,5-anisole methylene radical) pentanoyl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 8, with (E)-2-propyl group-3-(3,4,5-trimethoxyphenyl) vinylformic acid and 3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 132.5mg off-white color solid, receipts rate 59.7%.
1H-NMR(CDCl3):6.74(s,1H),6.58(s,2H),5.90(t,1H),3.80-3.90(m,15H),2.85(t,4H),2.60(t,2H),2.50(q,2H),1.54-1.58(m,4H),0.94(t,3H).EI-MS:m/z:445.3[M+H]+.
The preparation of embodiment 18:1-(5,6,7-trimethoxy-1-methyl isophthalic acid H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-methyl isophthalic acid H-Indoline-2-carboxylic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 146.2mg khaki color solid, receipts rate 85.0%.
1HNMR:(CDCl3,600MHz)δ6.95-6.98(m,1H),6.75(s,1H),6.74(s,1H),6.02(m,1H),4.16(s,3H),4.03(s,3H),3.96(t,2H),3.93(s,3H),3.87(s,3H),2.59-2.62(m,2H).EI-MS:m/z:345.2[M+H]+.
The preparation of embodiment 19:1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-ethyl-1H-Indoline-2-carboxylic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 157.0mg khaki color solid, receipts rate 87.6%.
1HNMR:(CDCl3,600MHz)δ6.92-6.95(m,1H),6.73(s,1H),6.71(s,1H),5.99(dt,1H),4.64(q,2H),4.04(s,3H),3.94(t,2H),3.90(s,3H),3.85(s,3H),2.57-2.60(m,2H),1.43(t,3H).EI-MS:m/z:359.2[M+H]+.
The preparation of embodiment 20:1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-butyl-1H-Indoline-2-carboxylic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 125.4mg khaki color solid, receipts rate 65.0%.
1HNMR:(CDCl3,600MHz)δ6.90-6.93(m,1H),6.71(s,1H),6.69(s,1H),5.96(dt,1H),4.61(q,2H),4.01(s,3H),3.92(t,2H),3.89(s,3H),3.82(s,3H),2.54-2.57(m,2H),1.71-1.74(m,2H),1.31-1.38(m,2H),0.96(t,3H).EI-MS:m/z:387.4[M+H]+.
The preparation of embodiment 21:1-(1-bromotrifluoromethane-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-bromotrifluoromethane-1H-Indoline-2-carboxylic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 112.3mg khaki color solid, receipts rate 51.3%.
1HNMR:(CDCl3,600MHz)δ6.93-6.96(m,1H),6.74(s,1H),6.72(s,1H),6.00(dt,1H),4.66(q,2H),4.06(s,3H),3.96(t,2H),3.93(s,3H),3.90(t,2H),3.87(s,3H),2.57-2.60(m,2H).EI-MS:m/z:400.3[M+H]+.
The preparation of embodiment 22:1-(1-benzyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-benzyl-1H-Indoline-2-carboxylic acid and 5,6-bis-hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 134.4mg khaki color solid, receipts rate 64.0%.
1HNMR:(CDCl3,600MHz)δ7.23-7.31(m,5H),6.91-6.95(m,1H),6.71(s,1H),6.68(s,1H),5.97(m,1H),5.69(s,2H),3.98(s,3H),3.92(t,2H),3.88(s,3H),3.82(s,3H),2.59-2.62(m,2H).EI-MS:m/z:421.2[M+H]+.
The preparation of embodiment 23:1-(1-methyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, replace 3,4,5-trimethoxy cinnamic acid with 5,6,7-trimethoxy-1-methyl isophthalic acid H-Indoline-2-carboxylic acid, obtain 163.1mg khaki color solid, receipts rate 86.1%.
1HNMR:(CDCl3,600MHz)δ7.08-7.09(m,1H),6.75(s,1H),6.74(s,1H),4.15(s,3H),4.01(s,3H),3.97(t,2H),3.92(s,3H),3.85(s,3H),2.66-2.69(m,2H).EI-MS:m/z:379.2[M+H]+.
The preparation of embodiment 24:1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, replace 3,4,5-trimethoxy cinnamic acid with 5,6,7-trimethoxy-1-ethyl-1H-Indoline-2-carboxylic acid, obtain 167.3mg khaki color solid, receipts rate 85.2%.
1HNMR:(CDCl3,300MHz)δ7.06-7.09(m,1H),6.73-6.75(m,2H),6.65(q,2H),4.04(s,3H),3.96(t,2H,),3.91(s,3H),3.85(s,3H),2.65-2.70(m,2H), 1.42(t,3H).EI-MS:m/z:393.2[M+H]+.
The preparation of embodiment 25:1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, replace 3,4,5-trimethoxy cinnamic acid with 5,6,7-trimethoxy-1-butyl-1H-Indoline-2-carboxylic acid, obtain 114.3mg khaki color solid, receipts rate 54.3%.
1HNMR:(CDCl3,300MHz)δ7.07-7.10(m,1H),6.73-6.75(m,2H),4.60(t,2H),4.03(s,3H),3.96(t,2H),3.91(s,3H),3.86(s,3H),2.65-2.71(m,2H),1.75-1.85(m,2H),1.33-1.41(m,2H),0.94(t,3H).EI-MS:m/z:421.2[M+H]+.
The preparation of embodiment 26:1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-ethyl-1H-Indoline-2-carboxylic acid and 3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 95.8mg khaki color solid, receipts rate 43.2%.
1HNMR:(CDCl3,300MHz)δ7.07-7.09(m,1H),6.72-6.74(m,2H),6.64(q,2H),3.76-4.03(m,15H),2.88-2.90(m,4H),2.65-2.70(m,2H),1.40(t,3H).EI-MS:m/z:444.1[M+H]+.
The preparation of embodiment 27:1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 8, with 5,6,7-trimethoxy-1-butyl-1H-Indoline-2-carboxylic acid and 3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone replace 3,4 respectively, 5-trimethoxy cinnamic acid and 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, obtains 91.2mg khaki color solid, receipts rate 38.7%.
1HNMR:(CDCl3,300MHz)δ7.06-7.09(m,1H),6.72-6.74(m,2H),4.59(t,2H),3.76-4.03(m,15H),2.87-2.89(m,4H),2.65-2.71(m,2H),1.75-1.85(m,2H),1.33-1.41(m,2H),0.94(t,3H).EI-MS:m/z:472.2[M+H]+.
Embodiment 28: the anti-tumor activity test of the compounds of this invention
The compound of the present invention has been carried out Cytostatic to tumor cell test, and test method adopts conventional mtt assay (as Lv Qiujun edits " new drug pharmaceutical research method ", 2007:242-243).
Cell strain selects A549 (human lung carcinoma cell), ZR-75-30 (human breast cancer cell), HCT116 (people's colon-cancer cell), frozen and go down to posterity by medicine industry research institute pharmacological evaluation room, Shanghai. Nutrient solution is that RPMI1640+15%NBS+ is dual anti-.
MTT solution is prepared: take MTT0.5 gram, be dissolved in 100mL phosphoric acid buffer (PBS) or without in phenol red substratum, with the bacterium of 0.22 μm of membrane filtration to remove in solution, put 4 DEG C and keep in Dark Place.
Sample liquid is prepared: after dissolving with DMSO (Merck), add PBS (-) be made into the solution of 100 μ g/mL or uniform suspension, then with the PBS of DMSO (-) dilution, final concentration is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL, 0.001 μ g/mL, 0.0001 μ g/mL.
The antineoplastic compound piperlongumine obtaining confirmation is made into reference substance solution with same condition.
Mtt assay: the 96 every holes of orifice plate add the cell suspension 100 μ L that concentration is 4-6 × 104/mL, put 37 DEG C, 5%CO2In incubator. After 24h, add sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C, 5%CO2Effect 72h. Every hole adds the MTT solution 20 μ L of 5mg/ml, adds lysate after effect 4h, and 100 μ L/ holes, put in incubator, surveys 570nmOD value by the full-automatic microplate reader of MK-2 after dissolving. Calculation of half inhibitory concentration IC50。
Test-results is in table 1; wherein; sample refers to Piperlongumine compounds (such as embodiment 14 i.e. (E)-3-chloro-1-(2-(3 of preparation in corresponding embodiment; 4; 5-anisole methylene radical) pentanoyl)-5,6-dihydropyridine-2 (1H)-one).
Table 1, first batch of test compounds anti tumor activity in vitro
Table 2, the 2nd batch of test compounds anti tumor activity in vitro
Embodiment 29:(E)-2-cyano group-3-(3,4,5-trimethoxyphenyl) acrylic acid preparation
By the 3 of 9.8 grams, 4,5-TMB and the cyanoacetic acid of 4.3 grams, the ammonium acetate of 3.9 grams, the toluene mixing post-heating back flow reaction 6 hours of 50 milliliters, a large amount of white solids is had to precipitate out, cooled and filtered, washing, a small amount of ethyl acetate washing, can obtain white solid 12.5 grams (95% receipts rate) after dry.
1HNMR:(DMSO-d6,300MHz)δ7.87(s,1H),δ7.42(wides,1H),δ7.29(s,2H),δ3.78(s,6H),δ3.70(s,3H)
Embodiment 30:(E)-2-butyl-(3,4,5-trimethoxyphenyl) acrylic acid preparation
By the diethyl phosphites of 2 milliliters (1.0eq) and 2.2 grams of sodium hydrogen (60%, 3.0eq.) it is dissolved in the glycol dimethyl ether of 50 milliliters, then drip and add 2-bromocaproic acid (1.0eq.), after dropwising, at room temperature stirring reaction, until without steam bubble, then 3 are added, 4, 5-TMB (1.0eq.), at room temperature stirring reaction 1 hour, then 5 milliliters of ethanol cancellation reactions are added, gained reaction solution is poured in 250 milliliters of frozen water, separate aqueous phase, by aqueous phase acid adjustment, after extraction into ethyl acetate, concentrated, pillar layer separation obtains 3.33 grams of off-white color solids (receipts rate 73%).
1HNMR:(CDCl3,300MHz) δ 7.72 (s, 1H), δ 6.67 (s, 2H), δ 3.89 (s, 3H), δ 3.88 (s, 6H), δ 2.56-2.61 (m, 2H), δ 1.58-1.65 (m, 2H), δ 1.40-1.48 (m, 2H), δ 0.95 (t, 3H).
The synthesis of embodiment 31:3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone
Lactan of restraining oneself 9.9 is dissolved in the methylene dichloride of 200 milliliters, under ice bath, the phosphorus pentachloride of 41.6 grams is added by part, after adding, reaction 10 minutes under 0 to 5 degree, then zinc iodide 1.0 grams is added, under nitrogen protection, room temperature reaction 1 hour, then the dichloromethane solution (32 grams of bromines are dissolved in the methylene dichloride of 100 milliliters) adding bromine is dripped, stir after dropwising and spend the night, it is cooled to 0 to 5 to spend, by in the frozen water pouring 500 milliliters into also careful for reaction, with dichloromethane extraction 5 times, anhydrous sodium sulfate drying, after adding with 4:1 (PE:EA) after concentrated, solid precipitates out, filter, 21.0 grams of solids can be obtained, it is directly used in the next step (82% receipts rate).
12.8 grams of 3,3-bis-bromine hexanolactams are dissolved in 70 milliliters of dry DMF, then add lithium chloride 4.0 grams, Quilonum Retard 7.0 grams, be warmed up to 130 degree react 8 hours after, boil off DMF, obtain white solid 6.8 grams (receipts rate 77%) through pillar layer separation.
1HNMR:(CDCl3,300MHz)δ7.05(t,1H),δ6.89(wides,1H),δ3.47-3.51(m,2H),δ2.40-2.46(m,2H).
Embodiment 32:(E) preparation of the chloro-1-of-3-(2-butyl-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
2-butyl-(3,4,5-trimethoxyphenyl) vinylformic acid (147mg, 0.5mmol) is joined in oxalyl chloride (254mg, 2mmol), reacts 4 hours under nitrogen protection, pressure reducing and steaming solvent. Then add the anhydrous tetrahydro furan of 5 milliliters under nitrogen protection, it is cooled to 0 degree, drip and add triethylamine (101mg, 1mmol). After dropwising, continue stirring reaction 15 minutes. Then will be dissolved in 5 milliliters of anhydrous tetrahydro furans 3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone (74mg, 0.5mmol) is added drop-wise in reaction flask. In stirred overnight at room temperature after dropwising. Adding methylene dichloride 30 milliliters, respectively with saturated ammonium chloride, saturated brine washing, anhydrous sodium sulfate drying, concentrated, pillar layer separation obtains 96.3mg off-white color solid, receipts rate 47.3%.
1HNMR:(CDCl3,300MHz)δ7.08(t,1H),δ6.77(s,1H),δ6.57(s,2H),δ3.97(t,2H),δ3.86(s,9H),δ2.58-2.66(m,4H),δ1.53-1.62(m,2H),δ1.32-1.40(m,2H),δ0.89(t,3H).EI-MS:m/z:407.89[M+H]+.
The preparation of embodiment 33:1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 167.2mg light yellow solid, receipts rate 73.2%.
1HNMR:(CDCl3, 600MHz) and δ 7.28-7.29 (m, 1H), δ 7.02-7.24 (m, 5H), 6.87 (s, 1H), 6.77 (s, 1H), 5.96 (s, 2H), δ 3.88-3.92 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 3.55 (s, 3H), 2.60-2.66 (m, 2H); EI-MS:m/z:455.37 [M+H]+.
Embodiment 34:(E) preparation of the bromo-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 32, it is possible to obtain 167.2mg light yellow solid, receipts rate 73.2%.
1HNMR:(CDCl3,300MHz)δ7.71(d,1H),δ7.41(d,1H),δ7.36(t,1H),δ6.81(s,2H),δ4.11(t,2H),δ3.90(s,6H),δ3.89(s,3H),δ2.50-2.56(m,2H).EI-MS:m/z:396.04[M+H]+.
Embodiment 35:(E) preparation of the bromo-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 32, it is possible to obtain 133.9mg light yellow solid, receipts rate 65.3%.
1HNMR:(CDCl3,300MHz)δ7.36(t,1H),δ6.89(s,1H),δ6.63(s,2H),δ3.97(t,2H),δ3.87(s,9H),δ2.57-2.63(m,2H),δ2.15(s,3H).EI-MS:m/z:410.06[M+H]+.
Embodiment 36:(E) preparation of the bromo-1-of-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 32, it is possible to obtain 142.0mg light yellow solid, receipts rate 67.1%.
1HNMR:(CDCl3,300MHz)δ7.36(t,1H),δ6.76(s,1H),δ6.58(s,2H),δ3.99(t,2H),δ3.88(s,9H),δ2.57-2.69(m,4H),δ1.16(t3H).EI-MS:m/z:424.08[M+H]+.
Embodiment 37:(E) preparation of the bromo-1-of-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 32, it is possible to obtain 123.3mg light yellow solid, receipts rate 56.4%.
1HNMR:(CDCl3, 300MHz) and δ 7.35 (t1H), δ 6.77 (d, 1H), δ 6.57 (s, 2H), δ 3.97 (t, 2H), δ 3.87 (s, 3H), δ 3.86 (s, 6H), δ 2.56-2.62 (m, 4H), δ 1.56-1.61 (m, 2H), δ 0.87-0.97 (m, 3H) .EI-MS:m/z:438.09 [M+H]+.
Embodiment 38:(E) preparation of the bromo-1-of-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one
According to the method for embodiment 32, it is possible to obtain 119.2mg light yellow solid, receipts rate 51.2%.
1HNMR:(CDCl3, 300MHz) and δ 7.35 (t, J=4.5Hz, 1H ,=CH), δ 6.77 (s, 1H ,=CH), δ 6.58 (s, 2H, ph), δ 3.98 (t, J=6.3Hz, 2H, NCH2),δ3.89(s,9H,3OMe),δ2.56-2.63(m,4H,CH2+CH2),δ1.54-1.59(m,2H,CH2),δ1.29-1.40(m,2H,CH2), δ 0.90 (t, J=7.2Hz, 3H, Me) .EI-MS:m/z:452.10 [M+H]+.
The preparation of embodiment 39:1-(5,6,7-trimethoxy-1-methyl isophthalic acid H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 137.3mg light yellow solid, receipts rate 64.9%.
1HNMR:(CDCl3,300MHz)δ7.36(t,1H),6.74(s,2H),4.15(s,3H),4.00(s,3H),3.96-3.98(m,2H),3.92(s,3H),3.86(s,3H),2.61-2.67(m,2H).EI-MS:m/z:425.05[M+H]+.
The preparation of embodiment 40:1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 148.0mg light yellow solid, receipts rate 67.7%.
1HNMR:(CDCl3,300MHz)δ7.35(t,1H),6.74(s,2H),4.64(q2H),4.04(s,3H),3.98(t,2H),3.91(s,3H),3.86(s,3H),2.61-2.67(m,2H),1.42(t,3H).EI-MS:m/z:439.07[M+H]+.
The preparation of embodiment 41:1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 120.0mg light yellow solid, receipts rate 53.2%.
1HNMR:(CDCl3,300MHz)δ7.35(t,1H),6.75(s,1H),6.74(s,1H),4.54-4.59(m,2H),4.03(s,3H),3.97(t,2H),3.91(s,3H),3.86(s,3H), 2.60-2.66(m,2H),1.80-1.88(m,2H),0.94(t,3H).EI-MS:m/z:453.08[M+H]+.
The preparation of embodiment 42:1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 113.3mg light yellow solid, receipts rate 48.7%.
1HNMR:(CDCl3,300MHz)δ7.36(t,1H),6.76(s,1H),6.74(s,1H),4.61(t,2H),4.04(s,3H),3.99(t,2H),3.92(s,3H),3.87(s,3H),2.62-2.68(m,2H),1.77-1.84(m,2H),1.40-1.44(m,2H),0.95(t,3H).EI-MS:m/z:467.10[M+H]+.
The preparation of embodiment 43:1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 174.3mg light yellow solid, receipts rate 69.8%.
1HNMR:(CDCl3,300MHz)δ7.34(t,1H),7.17-7.25(m,3H),7.04-7.06(m,2H),6.87(s,1H),6.79(s,1H,),5.96(s,2H),3.92(t,2H),3.88(s,3H),3.86(s,3H),3.55(s,3H),2.57-2.63(m,2H,).EI-MS:m/z:501.08[M+H]+.
The preparation of the chloro-1-of embodiment 44:3-(5,7-dimethoxy-1-methyl-6-(the third-2-alkynyloxy group)-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 112.4mg light yellow oil, receipts rate 55.8%.
1HNMR:(CDCl3,300MHz)δ7.10(t,1H),6.75(s,1H),6.74(s,1H), 4.77(d,2H),4.16(s,3H),4.04(s,3H),3.99(t,2H),3.86(s,3H),2.66-2.72(m,2H),2.50(t,1H).EI-MS:m/z:402.97[M+H]+.
The preparation of embodiment 45:1-(5,7-dimethoxy-1-methyl-6-(the third-2-alkynyloxy group)-1H-indole-2-carbonyl)-3-morpholine-5,6-two hydrogen-2 (1H)-pyridone
According to the method for embodiment 32, it is possible to obtain 103.8mg light yellow oil, receipts rate 45.8%.
1HNMR:(CDCl3,300MHz)δ6.77(s,1H),δ6.72(s,2H),δ6.02-6.03(m,1H),δ4.76(d,2H),δ4.15(s,3H),δ4.04(s,3H),δ3.83-3.89(m,5H),δ3.78-3.80(m,4H),δ2.89-2.91(m,2H),δ2.57-2.62(m,2H),δ2.49((t,1H).EI-MS:m/z:454.16[M+H]+.
Embodiment 46: the anti-tumor activity test of the compounds of this invention
The compound of the present invention has been carried out Cytostatic to tumor cell test, and test method adopts conventional mtt assay (as Lv Qiujun edits " new drug pharmaceutical research method ", 2007:242-243).
Cell strain selects A549 (human lung carcinoma cell), MDA-MB-231 (human breast cancer cell), HCT116 (people's colon-cancer cell), frozen and go down to posterity by medicine industry research institute pharmacological evaluation room, Shanghai. Nutrient solution is that RPMI1640+15%NBS+ is dual anti-.
MTT solution is prepared: take MTT0.5 gram, be dissolved in 100mL phosphoric acid buffer (PBS) or without in phenol red substratum, with the bacterium of 0.22 μm of membrane filtration to remove in solution, put 4 DEG C and keep in Dark Place.
Sample liquid is prepared: after dissolving with DMSO (Merck), add PBS (-) be made into the solution of 100 μ g/mL or uniform suspension, then with the PBS of DMSO (-) dilution, final concentration is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL, 0.001 μ g/mL, 0.0001 μ g/mL.
The antineoplastic compound piperlongumine obtaining confirmation is made into reference substance solution with same condition.
Mtt assay: the 96 every holes of orifice plate add the cell suspension 100 μ L that concentration is 4-6 × 104/mL, put 37 DEG C, 5%CO2In incubator. After 24h, add sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C, 5%CO2Effect 72h. Every hole adds the MTT solution 20 μ L of 5mg/ml, adds lysate after effect 4h, and 100 μ L/ holes, put in incubator, surveys 570nmOD value by the full-automatic microplate reader of MK-2 after dissolving. Calculation of half inhibitory concentration IC50。
Test-results is in table 3, wherein, sample refers to Piperlongumine compounds (such as embodiment 15 i.e. 1-(5,6 of preparation in corresponding embodiment, 7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone.
Table 3, the 3rd batch of test compounds anti tumor activity in vitro
Above experimental result shows, the compound of the present invention has good anti-tumor activity, and multiple compound is higher than existing antineoplastic compound piperlongumine, and therefore the compounds of this invention and salt thereof may be used for preparing antitumor drug.
More than show and describe the ultimate principle of the present invention, the advantage of main characteristic sum the present invention. The technician of the industry should understand; the present invention is not restricted to the described embodiments; the principle that the present invention is just described described in above-described embodiment and specification sheets; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention. The claimed scope of the present invention by appending claims and etc. jljl define.

Claims (3)

1. a similar thing of class piperlongumine, and pharmaceutical salts, described compound is selected from:
1-(5,6,7-trimethoxy-1-methyl isophthalic acid H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-bromotrifluoromethane-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-benzyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-methyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(1-ethyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone,
1-(1-butyl-5,6,7-trimethoxy-1H-indole-2-carbonyl)-3-morpholinyl-5,6-two hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-methyl isophthalic acid H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-ethyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-propyl group-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-butyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
1-(5,6,7-trimethoxy-1-benzyl-1H-indole-2-carbonyl)-3-bromo-5,6-bis-hydrogen-2 (1H)-pyridone,
(E) the chloro-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E)-3-morpholine-1-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E)-1-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E)-1-(2-(3,4,5-trimethoxy α-tolylene) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one,
(E) the chloro-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the chloro-1-of-3-(2-(3,4,5-trimethoxy α-tolylene) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one,
(E)-1-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-3-morpholinyl-5,6-dihydropyridine-2 (1H)-one,
(E)-3-morpholinyl-1-(2-(3,4,5-trimethoxy α-tolylene) butyryl radicals)-5,6-dihydropyridine-2 (1H)-one,
(E)-3-morpholinyl-1-(2-(3,4,5-trimethoxy α-tolylene) pentanoyl)-5,6-dihydropyridine-2 (1H)-one,
(E) the chloro-1-of-3-(2-butyl-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-methyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-ethyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-propyl group-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
(E) the bromo-1-of-3-(2-butyl-3-(3,4,5-trimethoxyphenyl) acryl)-5,6-dihydropyridine-2 (1H)-one,
The chloro-1-of 3-(5,7-dimethoxy-1-methyl-6-(the third-2-alkynyloxy group)-1H-indole-2-carbonyl)-3-chloro-5,6-bis-hydrogen-2 (1H)-pyridone, or
1-(5,7-dimethoxy-1-methyl-6-(the third-2-alkynyloxy group)-1H-indole-2-carbonyl)-3-morpholine-5,6-two hydrogen-2 (1H)-pyridone.
2. a similar thing of class piperlongumine according to claim 1, and pharmaceutical salts, described pharmaceutical salts, refers to and the salt that hydrochloric acid, nitric acid, Hydrogen bromide, toxilic acid, oxysuccinic acid or citric acid are formed.
3. a similar thing of class piperlongumine as claimed in claim 1 and pharmaceutical salts thereof are in the application prepared in antitumor drug.
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